MECHANISMS OF DISEASE Primary Open-Angle Glaucoma

Copyright © 2009 Massachusetts Medical Society. Glaucoma is a chronic, degenerative optic neuropathy that can be distinguished from most other forms of acquired optic neuropathy by the characteristic appearance of the optic nerve. In glaucoma, the neuroretinal rim of the optic nerve becomes progressively thinner, thereby enlarging the optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause is the loss of retinal ganglion cell axons, along with supporting glia and vasculature. The remaining neuroretinal rim retains its normal pink color. In other optic neuropathies, the optic-nerve tissue loses its pink color and cupping does not develop. A rare exception is arteritic anterior ischemic optic neuropathy, in which cupping can occur.1 Patients with glaucoma typically lose peripheral vision and may lose all vision if not treated. Although glaucoma frequently occurs without an elevation of intraocular pressure, the disease is nonetheless classified according to anterior-segment variations that can elevate intraocular pressure. The anterior segment of the eye has its own circulatory system, which nourishes the crystalline lens and cornea, both of which lack a blood supply. Aqueous humor, produced by the ciliary body, circulates throughout the anterior chamber and drains through the trabecular meshwork in the iridocorneal angle, which is the angle formed by the iris and cornea (Fig. 1).2 Elevated intraocular pressure does not result from increased aqueous humor production but rather from reduced aqueous outflow. The glaucomas are classified by the appearance of the iridocorneal angle. There are open-angle, closed-angle, and developmental categories, which are further divided into primary and secondary types. Primary open-angle glaucoma can occur with or without elevated intraocular pressure; the latter is sometimes called normal-tension glaucoma. Primary open-angle glaucoma includes both adult-onset disease (occurring after 40 years of age) and juvenile-onset disease (occurring between the ages of 3 and 40 years of age). Examples of secondary open-angle glaucomas include those associated with exfoliation or pigment-dispersion syndrome. Closed-angle glaucoma can be primary (e.g., pupillary block) or secondary (e.g., inflammatory or neovascular causes). Developmental forms of glaucoma include primary congenital glaucoma and glaucoma associated with syndromes (e.g., aniridia or the Axenfeld–Rieger syndrome). Primary open-angle glaucoma, the predominant form of glaucoma in Western countries, probably comprises several clinically indistinguishable diseases. In this review, we discuss primary open-angle glaucoma, in which the iridocorneal angle is open (unobstructed) and normal in appearance but aqueous outflow is diminished. We discuss the clinical features of primary open-angle glaucoma and mechanisms of elevated intraocular pressure and optic-nerve damage. To illustrate the mechanisms of elevated intraocular pressure, we focus on mutations in the myocilin (MYOC) gene. Approximately 4% of cases of adult-onset primary open-angle glaucoma and more than 10% of juvenile-onset cases are